Effective functioning of a medicinal ingredient in a formulation requires the reaching of the medicinal ingredient through blood vessels in the body to a target site. Capillaries, which are the narrowest among the blood vessels, are about 5 μm in diameter. Thus, in order for an organic compound with medicinal ingredients to pass through capillaries without causing occlusion, the organic compound needs to have a particle diameter of less than 5 μm.
Improved bioavailability for a formulation is very important in medical practice and pharmaceutical production because it reduces the dosage and thereby results in decreased side effects on the living body. Generally, the bioavailability for a formulation depends on the physicochemical properties, dosage form and route of administration of the drug. For example, while an oral formulation has the advantages of being convenient and causing little distress compared to an injectable (parenteral) preparation, it has the disadvantage of providing low bioavailability. The oral formulation enters the intestine through the stomach and duodenum, is absorbed mainly from the intestinal tract into the blood, and is transported to the liver through the portal vein. The oral formulation is partly decomposed by undergoing the action of gastric acid and the like or converted into a totally different substance by being metabolized in the liver during the course of passing through such a long route. One of the major reasons for the low bioavailability is that the oral formulation is less easily absorbed from digestive organs such as the intestine. To enhance the bioavailability for a formulation, it is necessary to decrease the size of the organic compound with medicinal ingredients to a level required to facilitate the absorption of the compound from the digestive organs into the blood.
Among formulations, more than a few contain a poorly water-soluble or water-insoluble organic compound as a medicinal ingredient. A formulation containing the poorly water-soluble or water-insoluble organic compound as a medicinal ingredient has previously been administered to the living body by decreasing the size of the organic compound using a method involving dissolving the organic compound in an organic solvent before dispensing, a method involving subjecting the organic compound to thermal dissolution before bringing the compound into emulsion (see e.g., Patent Literatures 1 and 2), a method involving converting the organic compound into fine grains having a size of the order of micron followed by mixing with water, or the like.
However, an organic solvent dissolving an organic compound can cause a medically undesirable event; thus, it is required to minimize the use of such an organic solvent. In addition, many of the organic compounds having medicinal ingredients each have almost the same melting point as the decomposition point thereof; thus, these organic compounds are liable to be decomposed at the same time as they are thermally dissolved and thereby to be changed into compounds incapable of being medicinal ingredients. Further, another problem is that it is difficult to use the method of thermal dissolution for organic compounds having high melting points.
With the recent progress of nanotechnology, attention has been drawn to a method for converting organic compounds into fine grains by finely pulverizing using mechanical means. For example, a method is known which involves fine-pulverizing a solid agrichemical active ingredient by a bead mill using beads composed of ceramic, glass, or the like (see e.g., Patent Literature 3). In addition, a method is also known which involves finely pulverizing an organic compound for use in ultraviolet absorbing agents using a pulverizing device such as a rotary ball mill (see e.g., Patent Literature 4). Further, a so-called solvent salt milling method, which is a method for finely pulverizing a pigment, is also known which involves subjecting crude dioxazine to wet fine-pulverizing in an inorganic salt and an organic liquid of an alcohol or a polyol (see e.g., Patent Literature 5).